The Pancreatic Duodenal Homeobox-1 Protein (Pdx-1) Interacts with Histone Deacetylases Hdac-1 and Hdac-2 on Low Levels of Glucose

Abstract

We have previously demonstrated that high concentrations of glucose stimulate insulin gene expression by causing hyperacetylation of histone H4 at the insulin gene promoter. Furthermore, we have shown that the glucose-mediated hyperacetylation of histone H4 depends on the recruitment of the histone acetyltransferase p300 by the beta cell-specific transcription factor Pdx-1. In this study, we demonstrate that the histone deacetylases Hdac-1 and Hdac-2 are rapidly recruited to the insulin promoter in the mouse insulinoma cell line MIN6 when cells are switched from high to low glucose media. Moreover, we demonstrate that the beta cellspecific homeodomain protein Pdx-1 interacts with histone deacetylases Hdac-1 and Hdac-2 at low levels of glucose. In vitro studies indicate that the interaction between Pdx-1 and Hdac-1 or Hdac-2 is direct and requires the C terminus of Pdx-1. Treatment of MIN6 cells with okadaic acid, which inhibits the activity of protein phosphatases, abolishes the interaction of Pdx-1 with Hdac-1 and Hdac-2 on low levels of glucose, suggesting the requirement of a dephosphorylation event for this interaction to occur. These data indicate that insulin gene expression is decreased on low levels of glucose by recruitment of Hdac-1 and Hdac-2 to the insulin promoter by the transcription factor Pdx-1.

SOX6 Attenuates Glucose-stimulated Insulin Secretion by Repressing PDX1 Transcriptional Actvity and Is Down-regulated in Hyperinsulinemic Obese Mice

“…It has been previously demonstrated that PDX1 specifically binds the proximal insulin promoter of MIN6 cells by a ChIP assay (47). 48 h following PDX1-siRNA treatment, we observed an 80% reduction in PDX1 occupancy at the insulin II promoter in MIN6 cells (Fig.…”

Histone Deacetylase (HDAC) Inhibition as a Novel Treatment for Diabetes Mellitus

“…These events appear to be necessary for preproinsulin transcription induced by glucose (96-100). Conversely, at low glucose levels where insulin production is shut off, the acetylation of histone H4 at the insulin promoter is abolished, correlating with recruitment of HDAC1 and -2 to the in- sulin promoter by Pdx1 (97,101). NeuroD1 also interacts with p300 and is acetylated by the p300-associated factor (PCAF).…”

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

“…Apart from interaction with transcription factors, Pdx1 also appears to recruit transcriptional co-activators (proteins that bridge Pdx1 to the basal transcriptional machinery), including CBP/ p300 [68,113,141,145,146], Set7/9 [147], Bridge-1 [148], PCIF1 [149], and histone deacetylases (HDACs) [150]. Once recruited, cofactors are believed to serve as a physical or functional "bridge" that allows Pdx1 to communicate with components of the basal transcriptional machinery.…”